Spread Of Melanoma Research Articles

LRG1 Promotes Metastatic Dissemination of Melanoma through Regulating EGFR/STAT3 Signalling.

Simple SummaryMelanoma is a highly metastatic and lethal form of skin cancer. Currently, there is no effective treatment available once melanoma cells spread to other parts of the body. Our study demonstrated that LRG1 regulates multiple aspects of melanoma metastasis through modulating EGFR/STAT3 signalling. Targeting LRG1 may offer an alternative way to control the metastatic spread of melanoma cells.Although less common, melanoma is the deadliest form of skin cancer largely due to its highly metastatic nature. Currently, there are limited treatment options for metastatic melanoma and many of them could cause serious side effects. A better understanding of the molecular mechanisms underlying the complex disease pathophysiology of metastatic melanoma may lead to the identification of novel therapeutic targets and facilitate the development of targeted therapeutics. In this study, we investigated the role of leucine-rich α-2-glycoprotein 1 (LRG1) in melanoma development and progression. We first established the association between LRG1 and melanoma in both human patient biopsies and mouse melanoma cell lines and revealed a significant induction of LRG1 expression in metastatic melanoma cells. We then showed no change in tumour cell growth, proliferation, and angiogenesis in the absence of the host Lrg1. On the other hand, there was reduced melanoma cell metastasis to the lungs in Lrg1-deficient mice. This observation was supported by the promoting effect of LRG1 in melanoma cell migration, invasion, and adhesion. Mechanistically, LRG1 mediates melanoma cell invasiveness in an EGFR/STAT3-dependent manner. Taken together, our studies provided compelling evidence that LRG1 is required for melanoma metastasis but not growth. Targeting LRG1 may offer an alternative strategy to control malignant melanoma.

Identification of Melanoma from Nevus Images

Melanoma is one of the fatal type skin cancers. The mortality rate is more severe than the present skin related diseases. Humans are prone to various diseases and are easily infected by them due to their adaptive and constrained lifestyle and melanoma is not an exception. Melanoma spreads faster and is less responsive to treatment in its later stages. Thus, harnessing the disease rate becomes more enigmatic and initial diagnosis is the need. Melanoma and nevus are akin and show analogous symptoms and traits. In order to overcome this, we use the technique of image processing to segregate Melanoma and nevus. The input image is processed in such way that the noise in the image (skin lesion) is removed using median filter and is segmented using improved K-means clustering. From the lesion necessary textural and chromatic features are extracted and a unique feature vector is formulated. Melanoma and Nevus are segregated using both Adaptive Neuro-Fuzzy inference System (ANFIS) and Feed-Forward Neural Network (FFNN). The skin images from DERMIS dataset is used in this work and it has 1023 skin images including 104 melanoma and 917 nevus images. Our proposed methodology provides efficient results having 97.3% and 96.8% accuracy for ANFIS and FFNN classifiers.

Small High-Risk Uveal Melanomas Have a Lower Mortality Rate.

Simple SummaryThe current paradigm concerning metastatic spread in uveal melanoma is that the critical point for dissemination occurs prior to presentation and that treatment of the primary tumor does not change outcome. However, we show that patients with small uveal melanomas with genetic characteristics typical for high risk for metastatic disease have a lower mortality rate from metastatic disease, if treated earlier. Our data demonstrate that such small melanomas are potentially lethal (like larger tumors), but that there is a window of opportunity to prevent life-threatening metastatic spread if actively treated, rather than being monitored, as is often done currently.Our aim was to determine whether size impacts on the difference in metastatic mortality of genetically high-risk (monosomy 3) uveal melanomas (UM). We undertook a retrospective analysis of data from a patient cohort with genetically characterized UM. All patients treated for UM in the Liverpool Ocular Oncology Centre between 2007 and 2014, who had a prognostic genetic tumor analysis. Patients were subdivided into those with small (≤2.5 mm thickness) and large (>2.5 mm thickness) tumors. Survival analyses were performed using Gray rank statistics to calculate absolute probabilities of dying as a result of metastatic UM. The 5-year absolute risk of metastatic mortality of those with small monosomy 3 UM was significantly lower (23%) compared to the larger tumor group (50%) (p = 0.003). Small disomy 3 UM also had a lower absolute risk of metastatic mortality (0.8%) than large disomy 3 UM (6.4%) (p = 0.007). Hazard rates showed similar differences even with lead time bias correction estimates. We therefore conclude that earlier treatment of all small UM, particularly monosomy 3 UM, reduces the risk of metastatic disease and death. Our results would support molecular studies of even small UM, rather than ‘watch-and-wait strategies’.

Using patient and melanoma tissue information to predict the risk of cancer spreading to the lymph nodes (CP‐GEP tool)

British Journal of DermatologyVolume 184, Issue 5 p. e169-e169 Plain Language Summary Using patient and melanoma tissue information to predict the risk of cancer spreading to the lymph nodes (CP-GEP tool) First published: 04 May 2021 https://doi.org/10.1111/bjd.19904AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinked InRedditWechat Abstract Linked Article: Mulder et al. Br J Dermatol 2021; 184:944–951. Melanoma is the most deadly type of skin cancer that develops in skin pigment cells. It affects about 132,000 people worldwide each year. The prognosis (predicting the outcome) in newly diagnosed patients strongly depends on the presence of spread from the skin into regional lymph nodes (glands) or even further into other parts of the body, such as the lungs and bones. Knowledge on whether the lymph nodes are affected by melanoma cells influences the type of cancer treatment given to patients. This is currently established by removal of the draining lymph node(s) of interest, a procedure that is known as a surgical sentinel lymph node biopsy. Cancer spread into the lymph node is present in roughly two out of 10 patients who undergo this procedure. Therefore, in the majority of patients this biopsy will not lead to a different treatment plan, but removing the lymph node(s) can lead to complications in one or two out of 10 patients. The CP-GEP tool was developed in a study of patients in the USA to calculate the risk of cancer spread into the lymph nodes. This study aimed to find out whether this tool could be of benefit in European patients as well. To calculate the risk (‘high’ or ‘low’), this tool combines information from the patient (age) and melanoma tissue (depth of the tumour and cancer genes). We compared the risk with the presence or absence of melanoma spread into the lymph nodes. This study shows that the CP-GEP tool can identify patients with melanoma who have a low risk of lymph node spread. In conclusion, the CP-GEP tool can be helpful to reduce the number of lymph node operations (and complications) in patients with melanoma. Volume184, Issue5May 2021Pages e169-e169 RelatedInformation

Two case reports of malignant melanoma rectum

Malignant melanoma of the rectum is an extremely rare disease. It typically presents in the fifth or sixth decade predominantly in female sex. The first symptoms are nonspecific such as bleeding, anal mass or pain. A timely diagnosis of melanoma is made even more difficult due to lack of obvious pigmentation and histologically amelanotic. Anorectal malignant melanoma spread along submucosal planes and are often beyond complete resection at the time of diagnosis. Prognosis is very poor. We present a rare case of malignant melanoma of rectum in a 21-year-old male, who was diagnosed at advanced stage, and a case of malignant melanoma in a 50-year-old male, who underwent abdominoperineal resection with permanent colostomy. Anorectal malignant melanoma is difficult to diagnose and prognosis is poor.

ESDN inhibits melanoma progression by blocking E-selectin expression in endothelial cells via STAT3

An interactive crosstalk between tumor and stroma cells is essential for metastatic melanoma progression. We evidenced that ESDN/DCBLD2/CLCP1 plays a crucial role in endothelial cells during the spread of melanoma. Precisely, increased extravasation and metastasis formation were revealed in ESDN-null mice injected with melanoma cells, even if the primary tumor growth, vessel permeability, and angiogenesis were not enhanced. Interestingly, improved adhesion of melanoma cells to ESDN-depleted endothelial cells was observed, due to the presence of higher levels of E-selectin transcripts/proteins in ESDN-defective cells. In accordance with these results, anticorrelation was observed between ESDN and E-selectin in human endothelial cells. Most importantly, our data revealed that cimetidine, an E-selectin inhibitor, was able to block cell adhesion, extravasation, and metastasis formation in ESDN-null mice, underlying a major role of ESDN in E-selectin transcription upregulation, which according to our data, may presumably be linked to STAT3. Based on our results, we propose a protective role for ESDN during the spread of melanoma and reveal its therapeutic potential.

Duodenal Metastasis From a Rectal Malignant Melanoma Primary: A Case Report

Duodenal melanoma constitutes a very small number of gastrointestinal malignant melanomas. The small intestine is a common site for the metastatic spread of cutaneous melanomas; however, its metastatic involvement from a primary rectal melanoma origin has seldom been reported. We present the histopathologic features of an unusual case of primary rectal melanoma metastasizing to the duodenum.

Post-operative follow-up of 150 patients with sentinel lymph node biopsy under tumescence local anesthesia.

Sentinel lymph node biopsy (SLNB) is useful for staging of patients with melanoma. Although SLNB is mostly performed under general anesthesia (GA), tumescence local anesthesia (TLA) can also be used. However, less data are available regarding feasibility of SLNB under TLA. Here we present a post-operative follow-up of 150 patients. We prospectively analyzed data from 150 patients with primary cutaneous malignant melanoma. We assessed pain, post-operative complications and patients' satisfaction after SLNB under TLA. 32% of the patients reported post-operative pain within the first 48h after SLNB. Seroma was the most frequent complication, as 29 seromas after SLNB were observed. Wound infection was observed in 3.3% of the patients. 98.7% of the patients were satisfied with SLNB under TLA. SLNB under TLA is a safe and feasible option and should be considered for patients with melanoma. Especially with multimorbid or elderly patients, the risks of GA can be avoided.

Expression of chondroitin sulfate proteoglycan4 (CSPG4) in melanoma cells is downregulated upon inhibition of BRAF.

Chondroitin sulfate proteoglycan 4 (CSPG4) is a multifunctional transmembrane proteoglycan involved in spreading, migration and invasion of melanoma. In addition to the activating BRAF V600E mutation, CSPG4 was shown to promote MAPK signaling by mediating the growth-factor induced activation of receptor tyrosine kinases. However, it remains elusive which factors regulate CSPG4 expression. Therefore, the aim of the present study was to examine whether BRAF and MEK inhibitors have an effect on the expression of CSPG4. We exposed a panel of BRAF-mutant CSPG4-positive or -negative melanoma cell lines to BRAF and MEK inhibitors. Protein levels of CSPG4 were analyzed by flow cytometry (FACS), immunofluorescence microscopy (IF), and western blotting. CSPG4 mRNA levels were determined by quantitative PCR (qPCR). The prolonged exposure of cells to BRAF and MEK inhibitors resulted in markedly reduced levels of the CSPG4 protein in permanent resistant melanoma cells as well as decreased levels of its mRNA. We did not observe increasing levels of CSPG4 shedding into the culture supernatants. In addition, patient-derived matched tumor samples following therapy with kinase inhibitors showed decreased numbers of CSPG4-positive cells as compared to pre-therapy tumor samples. Our results indicate that BRAF and MEK inhibition downregulates CSPG4 expression until the cells have developed permanent resistance. Our findings provide the basis for further investigation of the role of CSPG4 in the development of drug-resistance in melanoma cells.

Dedifferentiated and Undifferentiated Melanomas: Report of 35 New Cases With Literature Review and Proposal of Diagnostic Criteria.

Dedifferentiated melanoma (DM) and undifferentiated melanoma (UM) is defined as a primary or metastatic melanoma showing transition between conventional and undifferentiated components (DM) or lacking histologic and immunophenotypic features of melanoma altogether (UM). The latter is impossible to verify as melanoma by conventional diagnostic tools alone. We herein describe our experience with 35 unpublished cases to expand on their morphologic, phenotypic, and genotypic spectrum, along with a review of 50 previously reported cases (total: 85) to establish the diagnostic criteria. By definition, the dedifferentiated/undifferentiated component lacked expression of 5 routinely used melanoma markers (S100, SOX10, Melan-A, HMB45, Pan-melanoma). Initial diagnoses (known in 66 cases) were undifferentiated/unclassified pleomorphic sarcoma (n=30), unclassified epithelioid malignancy (n=7), pleomorphic rhabdomyosarcoma (n=5), other specific sarcoma types (n=6), poorly differentiated carcinoma (n=2), collision tumor (n=2), atypical fibroxanthoma (n=2), and reactive osteochondromatous lesion (n=1). In only 11 cases (16.6%) was a diagnosis of melanoma considered. Three main categories were identified: The largest group (n=56) comprised patients with a history of verified previous melanoma who presented with metastatic DM or UM. Axillary or inguinal lymph nodes, soft tissue, bone, and lung were mainly affected. A melanoma-compatible mutation was detected in 35 of 48 (73%) evaluable cases: BRAF (n=20; 40.8%), and NRAS (n=15; 30.6%). The second group (n=15) had clinicopathologic features similar to group 1, but a melanoma history was lacking. Axillary lymph nodes (n=6) was the major site in this group followed by the lung, soft tissue, and multiple site involvement. For this group, NRAS mutation was much more frequent (n=9; 60%) than BRAF (n=3; 20%) and NF1 (n=1; 6.6%). The third category (n=14) comprised primary DM (12) or UM (2). A melanoma-compatible mutation was detected in only 7 cases: BRAF (n=2), NF1 (n=2), NRAS (n=2), and KIT exon 11 (n=1). This extended follow-up study highlights the high phenotypic plasticity of DM/UM and indicates significant underrecognition of this aggressive disease among general surgical pathologists. The major clues to the diagnosis of DM and UM are: (1) presence of minimal differentiated clone in DM, (2) earlier history of melanoma, (3) undifferentiated histology that does not fit any defined entity, (4) locations at sites that are unusual for undifferentiated/unclassified pleomorphic sarcoma (axilla, inguinal, neck, digestive system, etc.), (5) unusual multifocal disease typical of melanoma spread, (6) detection of a melanoma-compatible gene mutation, and (7) absence of another genuine primary (eg, anaplastic carcinoma) in other organs.

S2223 Dead End in the Small Bowel: Rare Case of Small Bowel Melanoma Presenting as Melena

INTRODUCTION: Malignant melanoma accounts for only 1% of all malignant tumors of the small bowel. The majority are usually metastatic from the skin eye or anorectum. Less than 50 cases of truly primary small bowel melanomas have been described in literature with overt bleeding as a presenting complaint even rarer. We present such a case of an elderly man with middle gastrointestinal bleeding who was found to have unresectable small bowel melanoma on device assisted enteroscopy. CASE DESCRIPTION/METHODS: An 80-year-old man with stage IV Chronic kidney disease presented to the hospital with a few months of dark tarry stools and symptomatic iron deficiency anemia refractory to iron supplementation needing up to 7 transfusions. He did not endorse Non-steroidal anti-inflammatory drug use. An esophagoduodenoscopy and colonoscopy at an outside facility was unremarkable. Video capsule endoscopy showed hematin in the the proximal jejunum with a possible ulcer more distally. A single balloon enteroscopy revealed a 10 mm cratered jejunal ulcer with slight pigmentation in the base (Figure 1). This was biopsied. Pathology revealed malignant melanoma with BRAF V600E mutation. Subsequent positron emission tomography (PET) showed a 6 cm small bowel mass compatible with primary site and metastatic lesions in the mesentery, perihepatic and subdiaphragmatic region (Figure 2). Following tumor board discussion, he was referred for palliative radiotherapy. DISCUSSION: Primary mucosal melanoma most commonly arises from the anal canal (31.4%), rectum (22.2%) and oropharynx (33%). Only 2.3% of cases have been reported from the small bowel. Presence of melanocytes has not yet been demonstrated in the small intestine, and the origin of primary melanoma of the small intestine remains unknown. Blecker et al. suggested a strict criteria for the diagnosis of primary intestinal melanoma: no evidence of concurrent cutaneous lesions, absence of extraintestinal metastatic spread of melanoma, and presence of intramucosal lesions in the overlying intestinal epithelium. This form of melanoma is more aggressive and associated with worse prognosis. Other factors of poor prognosis include lymph node involvement, advanced age and failure to undertake surgical resection (which remains the primary treatment option). Our case highlights the importance of keeping a broad differential in patients presenting with middle GI bleeding and aggressively pursuing tissue diagnosis in such cases.Figure 1.: Proximal Jejunum ulcer.Figure 2.: PET scan image with metastatic melanoma.

Preliminary analysis of distinct clinical and biologic features of bone metastases in melanoma.

Melanoma disseminates to the skeletal system where it is then difficult to treat. Yet, there remains limited research investigating metastatic bone disease (MBD) in melanoma. Here, we evaluate whether there are distinct clinicopathologic variables at the time of primary melanoma diagnosis that predispose metastases to engraft bone, and we test the hypothesis that patients with MBD have different responses to treatment. Cutaneous melanoma patients enrolled in a prospective database were studied. Individuals with metastatic melanoma and bone metastases (M-Bone) were compared to those with metastatic disease but no M-Bone. Of the 463 (42.7%) patients, 198 with unresectable metastatic melanoma had M-Bone and 98 developed bone metastasis (bone mets) as first site. Progression-free survival and overall survival were significantly worse in patients with M-Bone compared to those without M-Bone (P < 0.001) independent of treatment modalities, and in patients whose melanoma spread to bone first, compared to those who developed first mets elsewhere (P < 0.001). Interestingly, patients with bone mets presented with primary tumors that had more tumor infiltrating lymphocytes (P < 0.001) and less often a nodular histologic subtype compared to patients without M-Bone (P < 0.001). Our data suggest that melanoma bone metastasis is a distinct clinical and biological entity that cannot be explained by generalized metastatic phenotype in all patients. The observed dichotomy between more favorable primary histopathologic characteristics and a grave overall prognosis requires more studies to elucidate the molecular processes by which melanomas infiltrate bone and to build a mechanistic understanding of how melanoma bone metastases yield such detrimental outcomes.

Glycopolymers for Efficient Inhibition of Galectin-3: In Vitro Proof of Efficacy Using Suppression of T Lymphocyte Apoptosis and Tumor Cell Migration.

The development of efficient galectin-3 (Gal-3) inhibitors draws attention in the field of anti-cancer therapy, especially due to the prominent role of extra- and intracellular Gal-3 in vital processes of cancerogenesis, such as immunosuppression, stimulation of tumor cells proliferation, survival, invasion, apoptotic resistance, and metastasis formation and progression. Here, by combining poly-LacNAc (Galβ4GlcNAc)-derived oligosaccharides with N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers, we synthesized multivalent glycopolymer inhibitors with a high potential to target extracellular and intracellular Gal-3. The inhibitory capabilities of the best conjugate in the studied series were in the nanomolar range proving the excellent Gal-3 inhibitory potential. Moreover, thorough investigation of the inhibitory effect in the biological conditions showed that the glycopolymers strongly inhibited Gal-3-induced apoptosis of T lymphocytes and suppressed migration and spreading of colorectal, breast, melanoma, and prostate cancer cells. In sum, the strong inhibitory activity toward Gal-3, combined with favorable pharmacokinetics of HPMA copolymers ensuring enhanced tumor accumulation via the enhanced permeability and retention effect, nominate the glycopolymers containing LacdiNAc-LacNAc (GalNAcβ4GlcNAcβ3Galβ4GlcNAc) tetrasaccharide as promising tools for preclinical in anti-cancer therapy evaluation.

Oral exposure to BDE-209 modulates metastatic spread of melanoma in C57BL/6 mice inoculated with B16–F10 cells

Polybrominated diphenyl ethers (PBDEs) are brominated, persistent and bioaccumulative flame retardants widely used in the manufacture of plastic products. Decabromodiphenyl ether (BDE-209) is the most prevalent PBDE in the atmosphere and found in human blood, breast milk and umbilical cord. In vitro studies showed that BDE-209 interferes with murine melanoma cells (B16F10), modulating cell death rates, proliferation and migration, important events for cancer progression. In order to evaluate if BDE-209 modulates metastasis formation in murine models, C57BL/6 mice were exposed to BDE-209 (0.08, 0.8 and 8 μg⁄kg) via gavage (5-day intervals for 45 days) (9 doses in total). Then, mice were inoculated with melanoma cells (B16–F10) at caudal vein receiving 4 additional doses of BDE-209. At 20th day post-cell inoculation, blood, lung, liver, kidney and brain were sampled for hematological, biochemical and morphological analyses. The slightly higher levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in the blood and pro-oxidant state in the liver of BDE-exposed mice indicated liver damage. Although the in vivo approach is for metastasis formation in the lung, they were unexpectedly observed in non-target organs (liver, brain, kidney and gonads). The similarity test showed high proximity among individuals from the control and a dissimilarity index between the control and exposed groups. The present data corroborate the known hepatotoxicity of BDE-209 to mice (C57BL/6) and demonstrate for the first time the increase of metastatic dissemination of B16F10 cells in vivo due to previous and continuous BDE-209 exposure, revealing possible implications of this organic compound with melanoma malignancy related traits.

Stem-Mesenchymal Signature Cell Genes Detected in Heterogeneous Circulating Melanoma Cells Correlate With Disease Stage in Melanoma Patients.

During the process of metastasis, cancer cells dissociate from primary tumors, migrate to distal sites, and finally colonize, eventually leading to the formation of metastatic tumors. These cancer cells, defined circulating tumor cells (CTCs) spreading through the blood stream, may develop metastatic lesions or remain dormant. Some emerging clinical evidence supports that some tumor cells may possess metastatic properties already in the earlier stages of tumorigenesis. Because the initiation and progression of vertical growth in human melanoma is fundamental to the notion of tumor virulence and progression, we decided to immune-magnetic collect and molecularly characterize circulating melanoma cells (CMCs) from melanoma patients AJCC staged = pT1b (i.e., transition from radial to vertical phase). CMCs are phenotypically and molecularly heterogeneous, thus we performed a “home-made Liquid-Biopsy,” by targeting the melanoma-associated-antigen, MCAM/MUC18/CD146, and/or the melanoma-initiating marker, ABCB5. We assessed a biomarker qualitative expression panel, contemplating the angiogenic-potential, melanoma-initiating and melanoma-differentiation drivers, cell-cell adhesion molecules, matrix-metallo-proteinases, which was performed on three enriched subpopulations from a total of 61 blood-samples from 21 melanoma patients. At first, a significant differential expression of the specific transcripts was documented between and within the CMC fractions enriched with MCAM-, ABCB5-, and both MCAM/ABCB5-coated beads, when analyzing two distinct groups: early AJCC- (stage I–II) and advanced- staged patients (stage II–IV). Moreover, in the early-AJCC staged-group, we could distinguish “endothelial,” CD45–MCAM+ enriched-, “stem” S-CMCs, CD45–ABCB5+ enriched- and a third hybrid bi-phenotypic CD45–MCAM+/ABCB5+ enriched-fractions, due to three distinct gene-expression profiles. In particular, the endothelial-CMCs were characterized by positive expression of genes involved in migration and invasion, whilst the stem CMC-fraction only expressed stem and differentiation markers. The third subpopulation isolated based on concurrent MCAM and ABCB5 protein expression showed an invasive phenotype. All three distinct CMCs sub-populations, exhibited a primitive, “stem-mesenchymal” profile suggesting a highly aggressive and metastasizing phenotype. This study confirms the phenotypic and molecular heterogeneity observed in melanoma and highlights those putative genes involved in early melanoma spreading and disease progression.

Tspan8 Drives Melanoma Dermal Invasion by Promoting ProMMP-9 Activation and Basement Membrane Proteolysis in a Keratinocyte-Dependent Manner.

Melanoma is the most aggressive skin cancer with an extremely challenging therapy. The dermal-epidermal junction (DEJ) degradation and subsequent dermal invasion are the earliest steps of melanoma dissemination, but the mechanisms remain elusive. We previously identified Tspan8 as a key actor in melanoma invasiveness. Here, we investigated Tspan8 mechanisms of action during dermal invasion, using a validated skin-reconstruct-model that recapitulates melanoma dermal penetration through an authentic DEJ. We demonstrate that Tspan8 is sufficient to induce melanoma cells’ translocation to the dermis. Mechanistically, Tspan8+ melanoma cells cooperate with surrounding keratinocytes within the epidermis to promote keratinocyte-originated proMMP-9 activation process, collagen IV degradation and dermal colonization. This concurs with elevated active MMP-3 and low TIMP-1 levels, known to promote MMP-9 activity. Finally, a specific Tspan8-antibody reduces proMMP-9 activation and dermal invasion. Overall, our results provide new insights into the role of keratinocytes in melanoma dermal colonization through a cooperative mechanism never reported before, and establish for the first time the pro-invasive role of a tetraspanin family member in a cell non-autonomous manner. This work also displays solid arguments for the use of Tspan8-blocking antibodies to impede early melanoma spreading and therefore metastasis.

Inhibitory effect of PAI-I in perifocal and resection line tissues on tumor growth in women with melanoma.

e22083 Background: The ability of malignant tumors to invasion and metastasis is associated with increased activity of the plasmin/plasminogen family proteases. The purpose of the study was to analyze changes in the plasmin/plasminogen system in tumors and adjacent tissues in patients with cutaneous melanoma in dependence on their gender. Methods: The study included 13 men and 22 women with cutaneous melanoma pT1-2N0M0. Levels of plasmin (PAP), content and activity of uPA, content and activity of tPA, content and activity of PAI were determined by ELISA in homogenates of melanoma (M), perifocal (P) and resection line (RL) tissues after surgical treatment. All patients gave a voluntary informed consent for the study. Skin tissues obtained from 20 non-cancer patients after plastic surgery served as the control. Results: The maximal PAP content in women was found in M – 16.5 times higher than in control, in RL – twice higher; PAP in all tissues of men was on average 7 times higher than in control. The content and activity of uPA and tPA in M were elevated in patients of both genders: in women by more than 3 times, in men by 4.9 and 3.7 times for uPA, respectively, and on average by 1.4 times for tPA. Increased content and activity of PAI-I were observed only in M of women by 74.6 and 2.3 times respectively, while PAI-I levels in men were similar to control values, and its activity was 2.9 times higher. Content and activity of PAI in P and RL tissues of men did not exceed the norm despite an increased activity of uPA and tPA, while in women they were elevated on average by 4 and 1.8 times, respectively. Conclusions: A local increase in the content and activity of the PAI-I plasminogen activator inhibitor in P and RL tissues only in women is a distinctive gender characteristics that can inhibit the spread of melanoma.

Targeting the cyclin-dependent kinase 5 in metastatic melanoma

The cyclin-dependent kinase 5 (CDK5), originally described as a neuronal-specific kinase, is also frequently activated in human cancers. Using conditional CDK5 knockout mice and a mouse model of highly metastatic melanoma, we found that CDK5 is dispensable for the growth of primary tumors. However, we observed that ablation of CDK5 completely abrogated the metastasis, revealing that CDK5 is essential for the metastatic spread. In mouse and human melanoma cells CDK5 promotes cell invasiveness by directly phosphorylating an intermediate filament protein, vimentin, thereby inhibiting assembly of vimentin filaments. Chemical inhibition of CDK5 blocks the metastatic spread of patient-derived melanomas in patient-derived xenograft (PDX) mouse models. Hence, inhibition of CDK5 might represent a very potent therapeutic strategy to impede the metastatic dissemination of malignant cells.

Measuring two proteins to help assess which melanomas are most likely to spread

Melanoma is the most deadly skin cancer, with a worldwide incidence that increases year on year. A major unmet need is the discovery of means through which to identify patients with early stage melanoma at high risk of disease progression, meaning it will spread elsewhere in the body. This UK study aimed to determine if the loss of two proteins, AMBRA1 and loricrin, in the skin (upper layer of skin epidermis) overlying a melanoma is able to predict which patients are at risk of disease spread. Initially, levels of AMBRA1 were assessed in melanoma biopsies from 79 patients. Results suggested a reduction or loss of AMBRA1 in the overlying epidermis was associated with a higher risk of disease spread. The ability to predict the risk of melanoma progression was improved by measuring combined levels of epidermal loricrin and AMBRA1 (eAMLo). By studying a further 379 melanoma samples with at least 10 years of follow‐up data (which shows what happened to the patient), the authors found that a stage I (early stage) melanoma in which eAMLo was lost was almost four times more likely to spread than a melanoma with maintained eAMLo. Importantly, patients in which eAMLo was retained (i.e. not lost) only had a 1.7% chance of disease progression. A melanoma's thickness is part of how its stage (progression) is measured, and currently, patients with a melanoma greater than 1mm thick are offered a further investigative test called sentinel lymph node biopsy (SLNB). However, a negative result from this invasive procedure does not provide any additional information about the chance of melanoma spread. Importantly, when eAMLo levels were assessed in melanomas eligible for SLNB, results further revealed eAMLo was better at identifying patients at truly low‐risk of disease spread than SLNB alone. Collectively, this study shows that measuring eAMLo will help to show a patient's true risk of a melanoma progression, which will help to guide their ongoing treatment and monitoring. This summary relates to the study: Epidermal autophagy and beclin 1 regulator 1 and loricrin: a paradigm shift in the prognostication and stratificatee on Cancer stage I melanomas

1942 A Rare Source of Gastrointestinal Bleeding Discovered With Capsule Endoscopy

INTRODUCTION: Melanoma accounts for 5% of all skin cancers, with lentigo maligna melanoma (LMM) accounting for 10–15% of melanomas. The LMM variety harbors a risk of invasive progression up to 20%. Studies have shown that the small bowel is a preferred site for melanoma metastasis due to its high vascularity, and approximately 60% of patients diagnosed with melanoma skin cancer will have gastrointestinal (GI) metastasis. The usual time for primary melanoma to GI metastasis is 60–90 months. Metastatic melanoma is a rare cause of GI bleeding but should be considered in all patients with history of cutaneous melanoma. This case report presents a man with history of LMM who presented with melena and capsule endoscopy identified small bowel metastasis of the primary cutaneous melanoma. CASE DESCRIPTION/METHODS: A 78-year-old man with medical history of cutaneous melanoma and Mohs surgical resection 2 years prior presented to the emergency department for melena over a 2-week duration. One year before this admission the patient presented with similar complaints and esophagogastroduodenoscopy (EGD) with colonoscopy did not yield a bleeding source. At admission he was hemodynamically stable with a hemoglobin of 9.7. Hemoccult testing in the emergency department was negative, but the patient was admitted for monitoring. Gastroenterology was consulted and because the patient had a stable hemoglobin during his stay without hemodynamic compromise, and in-light of recent negative EGD and colonoscopy, the decision was made to follow-up outpatient with capsule endoscopy (CE). On review of CE footage, the patient was found to have an ulcerated mass with active bleeding in the small bowel. Biopsy confirmed the mass was metastatic melanoma. The patient was referred to oncology who found multiple boney and liver metastases and started him on Nivolumab and Zometa. DISCUSSION: Metastatic melanoma spreads to the small bowel in 60% of cases. As in this case, metastatic melanoma to the small bowel can cause an occult GI bleed, or even massive bleeding and hematemesis, with some cases of intussusception also reported. Whatever the presentation, one should have a high index of suspicion of metastasis in patients with a history of cutaneous melanoma and new GI bleeding. Negative EGD and colonoscopy should prompt an investigation with CE to rule out metastatic lesions.